It is widely known that Renin-Angiotensin-Aldosterone system is closely connected with hypertensive pathogenesis through control of blood pressure and the water/electrolyte balance. Prevention and treatment of hypertension including essential hypertension and further congestive heart failure by controlling this system have been studied for a long time. As the controlling methods, there are i) inhibition of synthesis or secretion of renin which is thought to be situated at the most upstream position of the system, ii) renin-inhibition of the conversion of the renin substrate (angiotensinogen) to angiotensin (I), iii) inhibition of the angiotensin converting enzyme (ACE) which converts angiotensin (I) into angiotensin (II) having strong vasoconstriction action, aldosterone secretion stimulating action, sympathetic nerve function promoting action and the like, iv) blockade of angiotensin (II) receptor, v) activation of angiotensinase to accelerate the degradation of the produced angiotensin (II).
Among them, the study of ACE inhibitors is most advanced, and many drugs have been used for preventing or treating hypertension or congestive heart failure. However, since the ACE inhibitors are not selective and act toward other systems such as kalliklein-kinin system and the like, there is a clinical problem in that side effects such as skin rash and dry cough occur frequently. For this reason, many attempts to develop a renin inhibitor which is thought to be more selective have been tried but none have been successfully marketed.
On the other hand, since salarasin obtained by modifying the terminal part of angiotensin (II) has been found to have the antagonism to the receptor of angiotensin (II) by D. T. Pals et al., the study on a receptor antagonist (hereinafter referred to as Ang-II antagonist) has begun. Studies are directed to search for a nonpeptidic compound without partial agonist activity which can be administered orally, and has long-lasting action. The first reports are found in JP-A 54-148788, JP-A 56-71073, JP-A 57-98270 and JP-A 58-157768, but the pharmacological activity is about 1/10000 of the practical level. An increase in this activity to a practical level was first reported in EP-A 0253310 and EP-A 0291969, and the compound called as Dup753 is currently in clinical tests. ##STR2##
However, since this compound is usually produced as a mixture of regio-isomers (where the ratio depends on the reaction conditions), Dup753 can not be selectively synthesized unless a special process is used, and this is thought to be a problem for mass production. On the other hand, it has been recognized that an addition of a hydrophilic group on the 5-position of the imidazole ring is effective for increasing the pharmacological activity. This working hypothesis was compelled to be significantly modified by the finding of benzimidazoles shown in EP-A 039231717 (also reported in EP-A 0400835 and EP-A 0399732 later) and imidazopyridines (see EP-A 0399731, EP-A 0400974 and EP-A 01415886). ##STR3##
In addition, the present inventors have found that imidazobenzoquinones shown by the following formula have higher angiotensin (II) antagonist action and also have the vasodepressor activity in vivo tests, and filed a patent application (Japanese patent application No. 3-102639, 3-140057 and 3-205879). ##STR4##
On the other hand, them have been reported many compounds possessing a fused imidazole structure with a nitrogen containing saturated and/or unsaturated cyclic compound. For example, Warner Lambert has been reported the following compound (EP-A 245637). ##STR5## EQU R.sup.4 =--CH.sub.2 OR,--CH.sub.2 NR.sub.2,--CHO,--CN,--CO.sub.2 R
However, WL-19 reported therein has the selective affinity to different type Ang-II receptors and the vasopressor activity is far from practical use [Chang et al., Mol. Pharmacology, 24, 347 (1990)]. Merck has been reported a wide group of compounds as shown in the following (EP-A 400974, WO91/11999), and further a 7-membered (EP-A 401030) or 5-membered (EP-A 407102) nitrogen containing saturated compound. ##STR6## In particular, the compound wherein the fused ring is of the formula: ##STR7## which is disclosed in EP-A 4430974 and W091/11999 has a problem both in terms of stability and activity, in particular, in vivo activity, oral absorbability, weak hypotensive action and short duration of action, etc.
Takeda has been reported the following compound including a compound wherein the fused ring is of the formula: ##STR8##
Searle has been reported the following imidazopyridazine derivatives (WO91/19715). However, when R.sup.1 and/or R.sup.2 are hydroxy group in the compound, formation of ##STR9## bond via keto + enol tautomerism can be also considered. The structure of the Searle compounds is as follows: ##STR10##
The following compound reported by Roussel Uclaf (EP-A 46 1040) includes ##STR11## as the A ring. Also in this case, formation of ##STR12## via keto .revreaction. enol tautormerism can be considered. ##STR13##